The chemical name of the active substance ifosfamide is 3-(2-chloroethyl)-2-(chloroethylamino)-tetrahydro-2H-1,3,2-oxazaphosphorin -2-oxide, which has the formula: ##STR1##
In common with cyclophosphamide, ifosfamide belongs to the chemical group of oxazaphosphorins and is used therapeutically for the treatment of tumor diseases.
Ifosfamide is a white crystalline powder which has a melting point of 48.degree.-51.degree. C. and which is highly hygroscopic. Ifosfamide begins to sinter at temperatures below its melting point and must, therefore, be stored at temperatures that are as low as possible (room temperature and below). In addition, contact with moisture in the air should be avoided whenever possible.
Ifosfamide dissolves in water to the extent of about 10 percent by weight, but is only stable to a limited extent in aqueous solution (maximum of 3 to 4 hours at 20.degree. to 22.degree. C. or 36 hours at 4.degree. to 6.degree. C.)
Ifosfamide is exclusively administered parenterally. It normally is supplied in injection vials which contain 200 to 5000 mg of ifosfamide in the form of a sterile crystallizate. This active ingredient is dissolved in water for injection purposes before administration, at a concentration of at most 4%. This solution is suitable for intravenous injection. For intravenous short infusion, the ifosfamide solution is dissolved in 500 ml of Ringer's solution or similar infusion liquid. The duration of the infusion is generally about 30 minutes, but may be 1 to 2 hours. In the case of the 24-hour infusion, the ifosfamide solution is, for example, dissolved in a total of 3 liters of 5% dextrose sodium chloride solution.
Ifosfamide gives rise to numerous practical problems during preparation and processing. During preparation of the sterile crystallized ifosfamide there is a change of physical characteristics. In particular, dosage accuracy during filling is greatly impaired by variable flow properties.
The processing of ifosfamide is further impeded by its hygroscopic properties and low melting point. When stored for a long period of time, the sterile crystallizate sinters and the rate of dissolution decreases. When the ifosfamide begins to sinter, this is accompanied by a decrease in clear solubility and in the pH of the solution, with simultaneous yellow coloration. Once this happens, therapeutic use is generally no longer possible.